Acquired Immunodeficiency Syndrome (AIDS) is a transmissible disease caused by a retrovirus. The retrovirus responsible for AIDS was first identified by Barre-Sinoussi, F., et al, Science 220, 868-871, 1983 and Gallo, R. C., et al., Science 224:500-503, 1984, and related retroviruses have been isolated from patients in different areas. The accepted terminology for these isolates is human immunodeficiency virus (HIV), which has subtypes e.g. HIV type-1 and HIV type-2.
HIV produces a slow but usually progressive deterioration in the host immune system. Primary HIV infection represents the initial stage of AIDS when there is a burst of viral replication associated with dissemination in lymphoid tissue (Piatak et al, 1993, Science 1988, 239:586; Daar et al, 1991, N. Eng. J. Med. 1991, 324:961-964; and Fauci, 1993, Science 1993, 262:1011-1018). This acute HIV infection is largely an asymptomatic infection with a persisting generalized lymphadenopathy. A second stage in AIDS is a symptomatic HIV infection complicated by conditions attributable to compromised cellular immunity (e.g. thrush, listerosis, peripheral neuropathy). The third stage in AIDS is defined by laboratory criteria (reduced CD4+ cell numbers of percentage of total lymphocytes) and clinical criteria (characteristic opportunistic infections, neoplasms, central nervous systems disorders, and cachexia). Typically acute HIV infection lasts about 12 weeks; there is a period of clinical latency that lasts 5 to 10 years, and the patient survives about 2 years after a diagnosis of AIDS can be made. There is a progressive decrease in the number of CD4+ cells, as well as the destruction of CD4+ cells during these periods of the HIV infection (Hoxie, 1995, In Hoffman, R., et al., eds. Hematology. Basic Principles and Practice. Second Edition. New York. Churchill Livingstone, 1995:2011-2019).
The mechanisms by which HIV infection produces immunodeficiency is the subject of intensive investigations. It has been suggested that the decrease in CD4+ lymphocyte number and function involves direct effects of viral infection on mature and progenitor CD4 cells, as well as the destruction by cellular or humoral mechanisms of uninfected CD4 cells that display absorbed or processed viral antigens on their surface. Monocytes and macrophages which express the CD4 antigen are also targets for HIV infection. These cells of the reticuloendothelial system probably represent a major reservoir for virus production in vivo (Gendelman et al., 1989, AIDS 2:475; Embretson et al, 1993, Nature 362:359). Monocytes play a central role in the processing and presenting of antigens to T and B lymphocytes and they are able to migrate to the central nervous system. Therefore, infection of monocytes by HIV may play a role in the development of both immunologic and neurologic disease in infected individuals.
The use of intravenous immunoglobulin in the treatment of patients with HIV infections has been widely documented (See Schrappe-Bacher, M., Vox-Sang, 1990; Suppl 1:3-14; Wagner , N., et al. Arch. Dis. Child. 1992, Oct., 67(10): 1267-71; Brunkhorst, U. et al., Infection, 1990, 18(2):86-90; De Simone, C., et al, Immunopharmacol Immunotoxicol. 1991 13(3) 447-58; Gungor, T. et al., Eur. J. Pediatr., 1993 152(8): 650-4; Mofenson, L. M. et al., J. Acquir. Immune Defic. Syndr. 1993, 6(10): 1103-13; Mofenson, L. M. and Moye, J, Pediatr. Res. 1993 33(I Suppl): S80-7; discussion S87-9; Ersoy et al., Turk. J. Pediatr. 1992 34(4): 203-9; Shearer, W. T. et al, Ann N.Y. cad. Sci. 1993, 693:35-51; and WO 89/01339 to Cummins et al.). Intravenous immunoglobulin administration has been reported to be beneficial in reducing the rate of secondary opportunistic bacterial or viral infections in HIV-positive adults and children. It has also been reported to temporarily increase and/or maintain CD4+T-lymphocyte profiles in HIV-infected patients. However, this activity has not been consistently observed.
The serologic and immunologic effects of intravenous immunoglobulin on T-cell count appear to be dependent upon both the severity of the HIV infection and the duration of the study. Previous studies on the effect of intravenous immunoglobulin activity on CD4+ cell count and clinical efficacy were conducted in patients with early HIV infection (entry cell counts of.gtoreq.200/mm.sup.3) using relatively short treatment periods (.ltoreq.16 months). In contrast, serologic effects diminish with advancement of HIV infection (e.g. in patients with AIDS-related complex), and intravenous immunoglobulin was demonstrated to be serologically and clinically ineffective at 24 months. Therefore, the serological effects of intravenous immunoglobulin cannot solely account for its clinical actions, and the long-term benefits of intravenous immunoglobulin in HIV infections remains to be established.
Immune thrombocytopenia purpura (ITP) is a common complication of HIV infection. It can occur at any stage of its natural history, both in patients diagnosed with AIDS, those with AIDS-related complex, and those with HIV infection but without AIDS symptoms. ITP secondary to HIV infection involves both reduced production of platelets and antibody-mediated destruction of platelets by the reticuloendothelial system.
Rh(D) immunoglobulin has been used to treat HIV-associated ITP in adults and children (Gringeri, A., et al., Br. J. Haematol. 1992 80(3): 337-40; Rossi, E., et al., Haematologica 1991 76(2): 141-9; Landonio, G., et al., AIDS 1990 4(1): 29-34; Brusamolino, E., et al., Haemotologica 1989 74(1): 51-6; Cattaneo, M., et al., Blood 1989 73(1): 357); and Bussel et al., Blood, 1991, 77:1884-1893). The majority of patients treated with Rh(D) immunoglobulin respond with increased platelet counts, but the platelet response is temporary and lasts about 3 weeks. Rh(D) immunoglobulin treatment has been ineffective in Rh negative patients, and in all patients that have received a splenectomy prior to therapy.
PCT/US94/08312 (published on Feb. 23,1995 as No. WO 95/05196) describes a method for slowing the progression of HIV infection in patients by providing individuals with Rh antibody-antigen complexes or Rh antibody-antigen-complement complexes to inhibit binding of HIV-antibody complexes to follicular dendritic cells in lymph node tissue. However, one would not expect that these complexes would have the reported inhibitory effect since antibody complexes administered extraneously are not able to enter the lymphatic compartment to elicit the effect.